Cancer Chemother Pharmacol (2014) 74:861–865 DOI 10.1007/s00280-014-2565-y
ORIGINAL ARTICLE
A pilot study of S‑1‑based concurrent chemoradiotherapy in patients with biliary tract cancer Hee Man Kim · Kyong Joo Lee · Jihye Cha · Moon Jae Chung · Seungmin Bang · Jinsil Seong · Si Young Song · Seung Woo Park
Received: 22 April 2014 / Accepted: 1 August 2014 / Published online: 17 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose S-1 chemotherapy is effective against advanced biliary tract cancer. The purpose was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer. Methods Patients with pathologically-proven advanced biliary tract cancer were eligible. S-1 was orally administered at a dose of 40 mg/m2, twice daily from day 1 to 14 and from day 22 to 35; concurrent radiotherapy of 180–200 cGy per fraction was delivered in 25–28 fractions. After treatment completion, tumor response was evaluated by computed tomography. In the first stage of the optimal two-stage phase II design, 18 patients were required. Results Twenty patients were enrolled between August 2006 and February 2009. The median age was 62.5 years (range 45–77 years). The median follow-up time was 11.6 months (range 1.9–49.1 months). Fifteen patients H. M. Kim and K. J. Lee equally contributed to this work. H. M. Kim · K. J. Lee Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea J. Cha Department of Radiation Oncology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea M. J. Chung · S. Bang · S. Y. Song · S. W. Park (*) Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun‑gu, Seoul 120‑752, Republic of Korea e-mail: [email protected] J. Seong Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
(75 %) had extrahepatic cholangiocarcinoma, two patients (10 %) had intrahepatic cholangiocarcinoma, and three patients (15 %) had gallbladder cancer. After treatment, a partial response was achieved in three patients (15 %), and stable disease was achieved in 14 patients (70 %). The overall response rate was 15 %, and the disease stabilization rate was 85 %. There was no grade 4 toxicity or treatment-related death. The common grade 3 toxicities were thrombocytopenia (15 %), neutropenia (10 %), and nausea (10 %). The median progression-free survival and median overall survival were 5.9 months (range 2.2–9.5 months) and 10.8 months (range 1.1–20.4 months), respectively. Conclusions This study shows that S-1-based concurrent chemoradiotherapy is feasible and tolerable in patients with advanced biliary tract cancer. It will be further confirmed in a following large-scale phase II study. Keywords S-1 · Biliary tract cancer · Concurrent chemoradiotherapy · Pilot
Introduction Biliary tract cancer (BTC) is a relatively rare but highly fatal disease worldwide. BTC includes intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. The only curative treatment is surgical resection, but most of the patients with BTC are diagnosed with unresectable stages and receive medical treatment with a palliative aim. Currently, cisplatin plus gemcitabine combination chemotherapy has become the standard treatment for unresectable BTC based on the results of the ABC-02 trial [1]. However, the role of concurrent chemoradiotherapy is not well determined in BTC patients due to the limitations of clinical study. A few
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studies have shown survival improvements in BTC patients with 5-FU- or gemcitabine-based chemoradiotherapy compared with supportive care or chemotherapy alone [2, 3]. S-1 monotherapy is effective against advanced BTC [4–6]. S-1 is an oral anticancer drug composed of tegafur, 5-chloro-2,4-dihydroxypyridine, and oteracil potassium [7]. 5-Chloro-2,4-dihydroxypyridine is a competitive inhibitor of dihydropyrimidine dehydrogenase and maintains the concentration of 5-FU in the plasma and tumor tissues [8]. Oteracil potassium inhibits phosphorylation of 5-FU in the gastrointestinal tract and reduces serious gastrointestinal toxicities such as nausea, vomiting and diarrhea [8]. Recently, S-1 was approved for the treatment of various cancers, including BTC [9]. Furthermore, S-1-based chemoradiotherapy has been shown effective in treating advanced pancreatic cancer [10, 11]. However, there are no previous studies of S-1-based chemoradiotherapy in BTC. In this study, the primary aim was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer.
Patients and methods Study patients Enrolled patients were diagnosed with locally advanced biliary tract cancer at Severance Hospital in Seoul, Republic of Korea. Inclusion criteria were pathologically-proven BTC (intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer), measurable tumor, Eastern Cooperative Oncology Group (ECOG) performance scale between 0 and 2, adequate hematologic profile (neutrophil count ≥2,000/mm3; platelet count ≥100,000/mm3), and adequate renal function (serum creatinine ≤1.5 mg/100 mL). Prior adjuvant chemotherapy was allowed if recurrent or metastatic disease occurred 6 months after completion of treatment. Exclusion criteria were history of other chemotherapy or radiotherapy
ORIGINAL ARTICLE
A pilot study of S‑1‑based concurrent chemoradiotherapy in patients with biliary tract cancer Hee Man Kim · Kyong Joo Lee · Jihye Cha · Moon Jae Chung · Seungmin Bang · Jinsil Seong · Si Young Song · Seung Woo Park
Received: 22 April 2014 / Accepted: 1 August 2014 / Published online: 17 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose S-1 chemotherapy is effective against advanced biliary tract cancer. The purpose was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer. Methods Patients with pathologically-proven advanced biliary tract cancer were eligible. S-1 was orally administered at a dose of 40 mg/m2, twice daily from day 1 to 14 and from day 22 to 35; concurrent radiotherapy of 180–200 cGy per fraction was delivered in 25–28 fractions. After treatment completion, tumor response was evaluated by computed tomography. In the first stage of the optimal two-stage phase II design, 18 patients were required. Results Twenty patients were enrolled between August 2006 and February 2009. The median age was 62.5 years (range 45–77 years). The median follow-up time was 11.6 months (range 1.9–49.1 months). Fifteen patients H. M. Kim and K. J. Lee equally contributed to this work. H. M. Kim · K. J. Lee Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea J. Cha Department of Radiation Oncology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea M. J. Chung · S. Bang · S. Y. Song · S. W. Park (*) Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun‑gu, Seoul 120‑752, Republic of Korea e-mail: [email protected] J. Seong Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
(75 %) had extrahepatic cholangiocarcinoma, two patients (10 %) had intrahepatic cholangiocarcinoma, and three patients (15 %) had gallbladder cancer. After treatment, a partial response was achieved in three patients (15 %), and stable disease was achieved in 14 patients (70 %). The overall response rate was 15 %, and the disease stabilization rate was 85 %. There was no grade 4 toxicity or treatment-related death. The common grade 3 toxicities were thrombocytopenia (15 %), neutropenia (10 %), and nausea (10 %). The median progression-free survival and median overall survival were 5.9 months (range 2.2–9.5 months) and 10.8 months (range 1.1–20.4 months), respectively. Conclusions This study shows that S-1-based concurrent chemoradiotherapy is feasible and tolerable in patients with advanced biliary tract cancer. It will be further confirmed in a following large-scale phase II study. Keywords S-1 · Biliary tract cancer · Concurrent chemoradiotherapy · Pilot
Introduction Biliary tract cancer (BTC) is a relatively rare but highly fatal disease worldwide. BTC includes intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. The only curative treatment is surgical resection, but most of the patients with BTC are diagnosed with unresectable stages and receive medical treatment with a palliative aim. Currently, cisplatin plus gemcitabine combination chemotherapy has become the standard treatment for unresectable BTC based on the results of the ABC-02 trial [1]. However, the role of concurrent chemoradiotherapy is not well determined in BTC patients due to the limitations of clinical study. A few
13
862
studies have shown survival improvements in BTC patients with 5-FU- or gemcitabine-based chemoradiotherapy compared with supportive care or chemotherapy alone [2, 3]. S-1 monotherapy is effective against advanced BTC [4–6]. S-1 is an oral anticancer drug composed of tegafur, 5-chloro-2,4-dihydroxypyridine, and oteracil potassium [7]. 5-Chloro-2,4-dihydroxypyridine is a competitive inhibitor of dihydropyrimidine dehydrogenase and maintains the concentration of 5-FU in the plasma and tumor tissues [8]. Oteracil potassium inhibits phosphorylation of 5-FU in the gastrointestinal tract and reduces serious gastrointestinal toxicities such as nausea, vomiting and diarrhea [8]. Recently, S-1 was approved for the treatment of various cancers, including BTC [9]. Furthermore, S-1-based chemoradiotherapy has been shown effective in treating advanced pancreatic cancer [10, 11]. However, there are no previous studies of S-1-based chemoradiotherapy in BTC. In this study, the primary aim was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer.
Patients and methods Study patients Enrolled patients were diagnosed with locally advanced biliary tract cancer at Severance Hospital in Seoul, Republic of Korea. Inclusion criteria were pathologically-proven BTC (intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer), measurable tumor, Eastern Cooperative Oncology Group (ECOG) performance scale between 0 and 2, adequate hematologic profile (neutrophil count ≥2,000/mm3; platelet count ≥100,000/mm3), and adequate renal function (serum creatinine ≤1.5 mg/100 mL). Prior adjuvant chemotherapy was allowed if recurrent or metastatic disease occurred 6 months after completion of treatment. Exclusion criteria were history of other chemotherapy or radiotherapy
